Heterocycle compound, and production process and application thereof

Abstract

The compound of the present invention is a novel compound which has a specific heterocycle skeleton, particularly a pyrazolonaphthyridine or pyrazoloquinoline skeleton having an organic group (e.g., a carbocycle and a heterocycle) bonding through an alkylene group at 3-position and a carbocycle bonding at 5-position and has a phosphodiesterase IV inhibitory activity. At least one of the ring (the carbocycle or the heterocycle) bonding at 3-position of the pyrazolonaphthyridine skeleton and the carbocycle bonding at 5-position may have a halogenated alkyl group and/or a halogenated alkoxy group as a substituent. Such a compound or a salt thereof is useful as a phosphodiesterase IV inhibitor and the like. According to the present invention, a novel compound having a high phosphodiesterase IV inhibitory effect can be provided.

1. A compound represented by the following formula (1): 
       
         
           
           
               
               
           
         
         wherein the ring A represents a 6-membered heterocycle containing a nitrogen atom as a heteroatom; 
         the ring B represents a benzene ring; 
         —R 6 — represents a direct bond, 
         the ring C is an aromatic or nonaromatic ring and represents a heterocycle represented by the following formula (1c-1) or (1c-2): 
       
       
         
           
           
               
               
           
         
         
           wherein each of R 4  and R 5  represents a hydrogen atom;
 each of —R 6a — and —R 6b — corresponds to the —R 6 —, 
 the —R 6a — represents a direct bond, 
 the —R 6b — represents a direct bond, 
 r is 1, 
 s is 1; 
 
         
         the ring D represents a nitrogen atom-containing unsaturated 6-membered ring having an oxo group at 2-position; 
         R 1  represents an alkyl group comprising a substituent represented by the following formula (1e): 
       
       
         
           
           
               
               
           
         
         
           wherein the ring E represents a heterocycle containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, or a carbocycle; 
           R 7  represents a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a halogencontaining alkyl group, an alkoxy group, a halogen-containing alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an acyloxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an amino group, an N-substituted amino group, a ureido group, a sulfonic acid group, a sulfinic acid group, an alkylsulfonyl group, and a sulfonamide group; and t denotes 0 or 1; 
         
         R 2  represents a methyl group; 
         R 3  represents a substituent selected from the group consisting of a halogen-containing alkyl group and a halogen-containing alkoxy group; 
         p and q are the same or different and each denotes 0 or 1; 
         when the group R 1  is a straight chain C 1-3 alkyl group having a benzene ring, a thiophene ring, or a pyridine ring as the ring E, p is 0, and a fused ring comprising the ring A and the ring D is a fused ring represented by the following formula: 
       
       
         
           
           
               
               
           
         
          at least one of the ring B and the ring E has at least one member selected from the group consisting of a halogen-containing alkyl group and a halogen-containing alkoxy group as the substituent R 3  and/or R 7 ; and 
         R 4 , R 5 , —R 6 —, r, s, and t have the same meanings as defined above; or a salt thereof. 
       
     
     
       2. The compound or salt thereof according to  claim 1 , wherein
 in the formula (1e), the ring E is a cycloalkane ring or an arene ring, the group R 7  is a substituent selected from the group consisting of a halogen atom, an alkyl group, a halogen-containing alkyl group, an alkoxy group, and a halogen-containing alkoxy group. 
 
     
     
       3. The compound or salt thereof according to  claim 1 , wherein the group R 1  is a C 1-6 alkyl group comprising a substituent represented by the formula (1e), and
 in the formula (1e), the ring E is a cycloalkane ring or an arene ring, the group R 7  is a substituent selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a halogen-containing C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen-containing C 1-6 alkoxy group. 
 
     
     
       4. The compound or salt thereof according to  claim 1 , wherein at least one of the ring B and the ring E has at least one member selected from the group consisting of a fluoroalkyl group and a fluoroalkoxy group as the substituent R 3  and/or R 7 . 
     
     
       5. The compound or salt thereof according to  claim 1 , wherein at least one of the ring B and the ring E has at least one member selected from the group consisting of a straight chain or branched chain fluoroC 1-6 alkyl group and a straight chain or branched chain fluoroC 1-6 alkoxy group as the substituent R 3  and/or R 7 . 
     
     
       6. The compound or salt thereof according to  claim 1 , wherein
 the ring A is any one of the rings represented by the following formulae 
 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound or salt thereof according to  claim 1 , which is selected from the group consisting of
 a 3-(C 1-4 alkoxy-C 1-3 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 1-4 alkoxy-C 1-3 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 1-4 alkoxy-C 1-3 alkyl)-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-C 4-10 cycloalkyl-C 1-3 alkyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 4-10 cycloalkyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-C 4-10 cycloalkyl-C 1-3 alkyl-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(fluoroC 1-10 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(fluoroC  1-10 alkyl)-5-(fluoroC - 1-4  alkyl-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(fluoroC  1-10 alkyl)-5-(fluoroC  1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H) -one, 
 a 3-(phenyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H) -one, 
 a 3-(phenyl-C 1-3 alkyl)-5(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3 -c][1,8]-naphthyridin-4(5H) -one, 
 a 3-(phenyl-branched C 2-4 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(phenyl-branched C 2-4 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(phenyl-branched C 2-4 alkyl)-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(phenyl-C 1-3 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,7]-naphthyridin-4(5H)-one, 
 a 3-(phenyl-C 1-3 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,6]-naphthyridin-4(5H)-one, 
 a 3-(phenyl-C 1-3 alkyl)-5-phenyl-1H-pyrazolo[4,3-c][1,5]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl)C 1-3 alkyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5) -one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl)C 1-3 alkyl]-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl)C 1-3 alkyl]-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl) branched C 2-4 alkyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl) branched C 2-4 alkyl]-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkyl-phenyl) branched C 2-4 alkyl]-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl)C 1-3 alkyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl)C 1-3 alkyl]-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl)C 1-3 alkyl]-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl) branched C 2-4 alkyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl) branched C 2-4 alkyl]-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-[(fluoroC 1-4 alkoxy-phenyl) branched C 2-4 alkyl]-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo [4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 1-4 alkyl-phenyl-C 1-3 alkyl)-5-(fluoroC  1-4 alkyl-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 1-4 alkyl-phenyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(nitrophenyl-C 1-3 alkyl)-5-(fluoroC 1-4 -phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(nitrophenyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkoxy-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(C 1-4 alkoxy-phenyl-C 1-3 alkyl)-5-(fluoroC  1-4 alkyl-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5 H)-one, 
 a 3-(C 1-4 alkoxy-phenyl-C 1-3 alkyl)-5 -(fluoroC 1-4 alkoxy-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(halophenyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(halophenyl-C 1-3 alkyl)-5-(fluoroC 1-4 alkoxy-phenyl)- 1H-pyrazolo[4,3 -c][1,8]-naphthyridin4(5H)-one, 
 a 5-phenyl-3-(tetrahydro-2H-pyran-4-ylC 1-3 alkyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one which may have a fluoroC 1-4 alkyl group or a fluoroC 1-4 alkoxy group at the phenyl group of 5-position, 
 a 3-(thienylC 1-3 alkyl)-5-(fluoroC 1-4 alkyl-phenyl)- 1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 
 a 3-(thienylC  1-3 alkyl)-5-(fluoroC  1-4 alkoxy-phenyl)-1H- pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one; and 
 salts thereof. 
 
     
     
       8. A pharmaceutical composition containing a compound or a salt thereof recited in  claim 1 .